Our hypothesis is that fatigue of the diaphragm is intimately associated with changes in the mechanisms of neuromuscular transmission and of excitation and contraction of the muscle fibers of the diaphragm. We postulate further that the sites of fatigue will vary with the degree of development of the diaphragm and with different types of muscular contraction. Previous clinical work has shown the baboon to be an excellent model system for investigating human pulmonary disease. The specific aims of the proposal are to investigate mechanisms of diaphragmatic fatigue both in vivo and in vitro using premature (80 percent of gestation), newborn (100 percent of gestation) and adult baboons. Studies conducted in vivo will establish normal patterns of diaphragmatic movement using sonographic and electromyographic techniques. Measurements carried out in vitro will establish: (i) morphological properties of the diaphragm and its nervous connections. (ii) Physiological properties associated with normal and fatigued function of the diaphragm, including pre- and post- synaptic factors at the neuromuscular junction, mechanical properties of the fibers and the effects of muscle length and type of contraction on fatigability. (iii) Probable sites of fatigue, such as failure of neuromuscular transmission, excitation-contraction coupling or failure of the contractile machinery itself. (iv) Oxygen consumption of the normal and fatigued diaphragm in performing different types of work. This study should provide important insight into the relative importance of different types of muscular contraction, muscle length and energy expenditure in inducing diaphragmatic fatigue. In addition, the sites of fatigue at different stages of development should be identified and this information could form the basis for evaluating and treating diaphragmatic involvement in pulmonary distress at different ages. Data generated will also serve to indicate the applicability of results obtained in studies of small animal models to diaphragmatic fatigue in primates.